The nuclear hormone receptor superfamily of ligand activated transcription factors is present in various tissues, and responsible for a multitude of effects in these tissues.
The nuclear receptor (NR) superfamily presently comprises approximately 48 different proteins, of which 27 are ligand regulated, most of which are believed to function as ligand activated transcription factors, exerting widely different biological responses by regulating gene expression. Members of this family include receptors for endogenous small, lipophilic molecules, such as steroid hormones, retinoids, vitamin D and thyroid hormone.
The nuclear receptor (NR) superfamily includes the steroid nuclear receptor subfamily, including the mineralocorticoid receptor (MR) (or aldosterone receptor), the estrogen receptors (ER), ER alpha (ER-α) and ER beta (ER-β), the androgen receptor (AR), the progesterone receptors (PR), glucocorticoid receptors (GR) and others. Also closely related in structure are the estrogen related receptors (ERRs) ERR-α, ERR-β and ERR-γ. The steroid nuclear receptors perform important functions in the body, some of which are related to the transcriptional homeostasis of electrolyte and water balance, growth, development and wound healing, fertility, stress responses, immunological function, and cognitive functioning. The effects may be mediated by cytosolic, mitochondrial or nuclear events. Accordingly, compounds that modulate (i.e. antagonize, agonize, partially antagonize, partially agonize) the activity of steroid nuclear receptors are important pharmaceutical agents that have specific utility in a number of methods, as well as for the treatment and prevention of a wide range of diseases and disorders modulated by the activity of steroid nuclear receptors.
The biological actions of estrogens and antiestrogens are manifest through two distinct intracellular receptors, estrogen receptor alpha (ER-α) and estrogen receptor beta (ER-β). For instance, ER-β is present in, among other tissues, brain, bone, immune system, gastrointestinal tract, lung, ovary, endometrium, prostate, vasculature, urogenital tract, salivary gland, etc. The role of ER-β in these tissues has been confirmed by observed phenotypes in ER-β knockout mice. Pathologies in these tissues may be treated by administration of ER-β selective ligands.
The prevalence of metabolic diseases, such as obesity, insulin resistance and type II diabetes has increased dramatically in the past decade. For example, it is estimated that 400 million people were obese or overweight globally in 2008, and approximately two-thirds of Americans are overweight or obese, making obesity a serious health risk and economic burden to society. Obesity is not a stand-alone disease, as its emergence leads to various complications including type-2-diabetes mellitus (T2DM), hypertension, atherosclerosis and other cardiovascular diseases, osteoporosis and clinical depression [Lavie et al, 2009 J Am Coll Cardiol 53:1925-32; Fabricatore et al 2006 Annu Rev Clin Psychol 2:357-77]. Currently there are no effective pharmaceutical treatments for this pandemic problem. Although surgical procedures can reduce weight by 50-90%, it is restricted due to the risk of surgery and associated side effects. The best drugs currently in the market typically reduce weight by about 5-10% per year at most. Only two FDA approved drugs are available for treating over-weight indication: 1. Amphetamines (like phenteramine) and sibutramine that act on the hypothalamus to control appetite stimulation in the CNS. 2. Belviq® (lorcaserin) that is a 5-HT2C agonist that decreases food consumption and promotes satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus. 3. Orlistat that is a lipase inhibitor that blocks gastrointestinal absorption of fat and decreases energy uptake [Cooke et al 2006 Nat Rev Drug Discov 5:919-31]. Common side effects associated with these drugs including tachycardia, hypertension, fecal incontinence and/or cardiac valvopathy, making anti-obesity drug development of paramount importance. Therefore, there is a need in the art for more effective and safe drugs to treat conditions such as obesity, and other related conditions and metabolic disorders.
Obesity is a heterogeneous disease which occurs when energy uptake exceeds energy expenditure. Though the etiology of obesity remains uncertain, several mechanisms such as alterations in feeding behavior, signals in the hypothalamus, levels of leptin, adipokines secreted by white adipose tissue (WAT), neuropeptides and neurotransmitters that control behavior, hormonal changes associated with age, inflammatory signals in adipose, stress and others trigger the onset of obesity [Yu et al 2009 Forum Nutr 61:95-103; Rother et al 2009 Dtsch Med Wochenschr 134:1057-9; Reisin et al 2009 Med Clin North Am 93:733-51].
Increase in the incidence of post-menopausal obesity, visceral obesity at andropause and gender differences in the incidence of metabolic diseases indicate the importance of the nuclear hormone receptor (NR) superfamily in regulating body weight [Allende-Vigo M Z 2008 P R Health Sci J 27:190-5; Geer et al 2009 Gend Med 6 Suppl 1:60-75]. Many of the NRs play pivotal roles in regulating the emergence of metabolic diseases. Activation of bile acid NRs such as Farnesoid X Receptor (FXR), Constitutive Androstane Receptor (CAR) and Pregnane X Receptor (PXR) promotes weight loss and also increases insulin sensitivity [Thomas et al 2008 Nat Rev Drug Discov 7:678-93; Cariou B et al 2007 Trends Pharmacol Sci 28:236-43]. Similarly, Estrogen Related Receptors (ERRα, ERRβ and ERRγ) play significant roles in increasing energy expenditure, reducing adipogenesis and body weight gain [Ariazi E A et al 2006 Curr Top Med Chem 6:203-15]. Other members of the NR belonging to the Peroxisome Proliferator Activated Receptor (PPARs) and Estrogen Receptors (ERs) also play a role in maintenance of blood glucose and body fat, making the NRs an attractive target to prevent/treat obesity and metabolic diseases [Kintscher U et al 2009 Curr Opin Investig Drugs 10:381-7; Beekum O et al 2009 Obesity (Silver Spring) 17:213-9; Billin A N 2008 Expert Opin Investig Drugs 17:1465-71; Barros R P et al 2006 Trends Mol Med 12:425-31].
Cardiovascular diseases such as hypertension, coronary heart disease (CHD), and atherosclerosis have a higher incidence in post-menopausal women than in premenopausal women. This loss of cardiovascular protection is attributed to the deficiency in circulating estrogen levels in the post-menopausal women. Hormone replacement therapy (HRT) can markedly reduce the risk of cardiovascular disease in post-menopausal women. However, the use of HRT for cardioprotection is limited due to the increased incidence of endometrial cancer in women and gynecomastia in men.
Cardiac hypertrophy, ventricular hypertrophy, left ventricular hypertrophy, cardiomegaly, cardiac fibrosis, cardiomyopathy, dilated cardiomyopathy, myocardial infarction and cardiac failure are pathological reactions to cardiovascular diseases like hypertension, CHD and atherosclerosis. Increased arterial vascular resistance results in cardiomyocyte hypertrophy. If the underlying cause is not controlled, cardiac hypertrophy progresses to dilation, apoptotic thinning of myocytes, and ultimately heart failure. Treatments that reduce arterial vascular resistance and thus hypertension, may aid in the prevention or treatment of conditions associated with cardiovascular disease. Cardioprotective effects of estrogen have now been known for a long time (Schrepfer, S., Deuse T., et al. Menopause (2006) 13(3): 489-499). However, the isoform that is involved in this protective effect is still under debate. Literature evidence to support the involvement of both the isoforms is available. Both circulating and exogenously administered estrogens reduce vasoconstriction of the pulmonary artery, suggesting application in hypertension. Studies with propylpyrazaole triol (ERα selective agonist) and diarylproprionitrile (ERβ selective agonist) suggested that both ER isoforms are involved (Yu H P, Shimizu T, et al. J. Mol. Cell. Cardiol. (2006) 40(1): 185-194; Ba Z F, Chaudry I H. Am. J. Physiol Heart Circ. Physiol. (2008) 295(5): H2061-H2067). However, due to their lack of effects on reproductive tissues, ERβ selective agonists may be a preferable strategy for hypertension. In addition, extensive literature that suggests the involvement of ERβ in myocardial protection is available. Knockout of ERβ (ERβKO) led to increased mortality and aggravation of heart failure after myocardial infarction in mice (Pelzer T, Loza P A, et al. Circulation (2005) 111(12): 1492-1498). Similarly, after reperfusion/ischemic injury, ERβKO mice demonstrated a delayed cardiac recovery compared to wildtype or ERαKO mice.
ER-β in some cases functions as an antagonist of ER-α through heterodimerization with ER-α. For instance, agonists of ER-β may block the proliferative influence of ER-α in tissues such as prostate and breast where ER-α is known to promote neoplasia. In addition to its anti-ER-α mediated growth inhibition, ER-β autonomously inhibits proliferation and promotes differentiation of prostate and other cancers. ER-β is also believed to antagonize the proliferative effects AR in prostatic tissues. Prostatic hypertrophy and hyperplasia/dysplasia may result from a combination of androgenic stimulation of proliferation and/or failed activation of ER-β by locally synthesized estrogens. This hypertrophy or hyperplasia/dysplasia often leads to a variety of prostatic maladies such as BPH, prostatic inflammatory atropy (a precursor to neoplasia), PIN, and CaP. Administration of exogenous ER-β agonists can be expected to provide prostatic anti-proliferation thereby being beneficial in the prevention or treatment of these prostatic diseases. Additionally, decreased side effects can be expected for ER-β selective agents compared to isoform nonselective ligands for treating many of these diseases.
Compounds that act as estrogen receptor ligands are, therefore, useful in treating a variety of conditions and disorders. Selective estrogen receptor modulators (estrogen receptor ligands, such as ERβ agonists) are disclosed, for example, in U.S. Patent Publication No. 2009/0030036.
Hormones are important regulators of adipose function and epidemiological studies suggest that estrogens regulate metabolism and fat distribution. The presence of ER-α and ER-β, the two receptors that mediate the actions of estradiol, in adipose tissue implicates a direct role of the ligands in adipose function. Moreover, the observed gender and age differences in the discovery of brown adipose tissue (BAT) in humans point towards the possibility that circulating estradiol levels may be an important contributor toward the development of BAT [Cypess A M et al. 2009 N Engl J Med 360:1509-17]. Studies with individual ER Knockout (KO) mice indicated the importance of these isoforms in maintaining lipid and glucose homeostasis [Harris H A 2007 Mol Endocrinol 21:1-13]. ER-αKO mice exhibit insulin resistance, whereas, high fat diet fed ER-βKO mice demonstrate a higher magnitude of obesity than wildtype mice [Foryst-Ludwig A et al 2008 PLoS Genet 4:e1000108]. Though some of these studies speculated that estrogenic control of body weight is mediated by ER-β, it is still not clear which isoform mediates the beneficial effects of estradiol on body fat, glucose and cholesterol [Pallottini V et al 2008 Infect Disord Drug Targets 8:52-60; Liang Y Q et al 2002 Int J Obes Relat Metab Disord 26:1103-9].